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Summary Background Little is known about how to implement antiretroviral treatment programmes in resource-limited countries. We assessed the UNAIDS/Uganda Ministry of Health HIV Drug Access Initiative—one of the first pilot antiretroviral programmes in Africa—in which patients paid for their medications at negotiated reduced prices. Methods We assessed patients' clinical and laboratory information from August, 1998, to July, 2000, from three of the five accredited treatment centres in Uganda, and tested a subset of specimens for phenotypic drug resistance. Findings 912 patients presented for care at five treatment centres. We assessed the care of 476 patients at three centres, of whom 399 started antiretroviral therapy. 204 (51%) received highly active antiretroviral therapy (HAART), 189 (47%) dual nucleoside reverse transcriptase inhibitors (2NRTI), and six (2%) NRTI monotherapy. Median baseline CD4 cell counts were 73 cells/μL (IQR 15–187); viral load was 193 817 copies/mL (37 013–651 716). The probability of remaining alive and in care was 0·63 (95% CI 0·58–0·67) at 6 months and 0·49 (0·43–0·55) at 1 year. Patients receiving HAART had greater virological responses than those receiving 2NRTI. Cox's proportional hazards models adjusted for viral load and regimen showed that a CD4 cell count of less than 50 cells/μL ( vs 50 cells/μL or more) was strongly associated with death (hazard ratio 2·93 [1·51–5·68], p=0·001). Among 82 patients with a viral load of more than 1000 copies/mL more than 90 days into therapy, phenotypic resistance to NRTIs was found for 47 (57%): 29 of 37 (78%) who never received HAART versus 18 of 45 (40%) who received HAART (p=0·0005). Interpretation This pilot programme successfully expanded access to antiretroviral drugs in Uganda. Identification and treatment of patients earlier in the course of their illness and increased use of HAART could improve probability of survival and decrease drug resistance.

1and new resources have become available. 2 Although expense, feasibility, and effective delivery remain formidable barriers, public health and technical agencies have started to re-examine their assumptions and to discuss use of antiretroviral drugs in poorly resourced environments. 3 Data lending support to use of antiretroviral treatment in poorly resourced regions are few. Even in well resourced countries, clinicians still do not have evidencebased answers to simple issues such as: when to start antiretrovirals, how to monitor their therapeutic and toxic effects, and in what sequence to use them. Answers to such issues are greatly needed to speed up delivery of antiretrovirals to the populations most in need of treatment. As a working group convened by the Rockefeller Foundation, we outline an urgent research agenda that attempts to identify gaps in knowledge and to prioritise issues affecting access to treatment for the tens of millions of adults living with HIV/AIDS in poorly resourced regions. Answers to many of these questions will also benefit patients in well resourced regions. We do not address the equally important issues about use of antiretrovirals in infants and children and of prevention of mother-to-child transmission. When should antiretroviral treatment be started? Use of antiretroviral treatment is straightforward in adults with symptomatic HIV-1 disease or CD4+ counts of 200 or less, 4–6 but whether asymptomatic adults with more

Summary Background Co-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa; whether benefits occur alongside combination antiretroviral therapy (ART) is unclear. We estimated the effect of prophylaxis after ART initiation in adults. Methods Participants in our observational analysis were from the DART randomised trial of management strategies in HIV-infected, symptomatic, previously untreated African adults starting triple-drug ART with CD4 counts lower than 200 cells per μL. Co-trimoxazole prophylaxis was not routinely used or randomly allocated, but was variably prescribed by clinicians. We estimated effects on clinical outcomes, CD4 cell count, and body-mass index (BMI) using marginal structural models to adjust for time-dependent confounding by indication. DART was registered, number ISRCTN13968779. Findings 3179 participants contributed 14 214 years of follow-up (8128 [57%] person-years on co-trimoxazole). Time-dependent predictors of co-trimoxazole use were current CD4 cell count, haemoglobin concentration, BMI, and previous WHO stage 3 or 4 events on ART. Present prophylaxis significantly reduced mortality (odds ratio 0·65, 95% CI 0·50–0·85; p=0·001). Mortality risk reduction on ART was substantial to 12 weeks (0·41, 0·27–0·65), sustained from 12–72 weeks (0·56, 0·37–0·86), but not evident subsequently (0·96, 0·63–1·45; heterogeneity p=0·02). Variation in mortality reduction was not accounted for by time on co-trimoxazole or current CD4 cell count. Prophylaxis reduced frequency of malaria (0·74, 0·63–0·88; p=0·0005), an effect that was maintained with time, but we observed no effect on new WHO stage 4 events (0·86, 0·69–1·07; p=0·17), CD4 cell count (difference vs non-users, −3 cells per μL [−12 to 6]; p=0·50), or BMI (difference vs non-users, −0·04 kg/m 2 [−0·20 to 0·13); p=0·68]. Interpretation Our results reinforce WHO guidelines and provide strong motivation for provision of co-trimoxazole prophylaxis for at least 72 weeks for all adults starting combination ART in Africa. Funding UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.